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Abstract:

The present invention provides a piperazine compound represented by
Formula (I) or a salt thereof,
##STR00001##
wherein X represents CH or an N atom; R1 represents C1-6
alkyl; R2 represents C1-6 alkyl that may have one or more
substituents, C2-6 alkenyl that may have one or more substituents,
--(C═O)--N(R3)(R4), or --(C═O)--OR5, R3 and
R4 are the same or different, and each represents hydrogen or
C1-6 alkyl that may have one or more substituents; or R3 and
R4, taken together with a nitrogen atom to which R3 and R4
are attached, may form a saturated heterocyclic group; and R5
represents hydrogen or C1-6 alkyl that may have one or more
substituents or aralkyl.

Claims:

1. A piperazine compound represented by Formula (I) or a salt thereof,
##STR00069## wherein X represents CH or an N atom; R1 represents
C1-6 alkyl; R2 represents C1-6 alkyl that may have one or
more substituents, C2-6 alkenyl that may have one or more
substituents, --(C═O)--N(R3)(R4), or --(C═O)--OR5,
R3 and R4 are the same or different, and each represents
hydrogen or C1-6 alkyl that may have one or more substituents; or
R3 and R4 taken together with a nitrogen atom to which R3
and R4 are attached, may form a saturated heterocyclic group; and
R5 represents hydrogen or C1-6 alkyl that may have one or more
substituents or aralkyl.

2. The piperazine compound according to claim 1 or a salt thereof,
wherein X represents CH or an N atom; R1 represents methyl or ethyl;
R2 represents C1-3 alkyl that may have one or more carbamoyl or
unsaturated heterocyclic groups as substituents, propenyl that may have
one or more carbamoyl groups as substituents,
--(C═O)--N(R3)(R4), or --(C═O)--OR5; one of
R3 and R4 represents hydrogen and the other represents
C1-6 alkyl that may have one or more saturated or unsaturated
heterocyclic groups as substituents; or R3 and R4, taken
together with a nitrogen atom to which R3 and R4 are attached,
may form pyrrolidinyl, piperidinyl, piperazinyl, and morpholino; and
R5 represents hydrogen, methyl, ethyl, tert-butyl, or benzyl.

3. The piperazine compound according to claim 1, or a salt thereof,
wherein X represents CH or an N atom; R1 represents methyl; R2
represents C1-3 alkyl that may have any one of morpholinocarbamoyl
and triazolyl groups as a substituent, --(C═O)--N(R3)(R4),
or --(C═O)--OR5; and the triazolyl may have one or two C1-6
alkyl as substituents; one of R3 and R4 represents hydrogen and
the other represents C1-3 alkyl that may have one or more morpholino
or pyridyl groups as substituents; or R3 and R4, taken together
with a nitrogen atom to which R3 and R4 are attached, may form
morpholino; and R5 represents hydrogen.

4. The piperazine compound according to claim 1 or a salt thereof,
wherein X represents CH; R1 represents methyl; R2 represents
linear C1-3 alkyl that may have any one of 1,2,3-triazolyl,
1,2,4-triazolyl, and 3,5-dimethyl-1,2,4-triazolyl as a substituent,
--(C═O)--N(R3)(R4), or --(C═O)--OR5; R3 and
R4, taken together with a nitrogen atom to which R3 and R4
are attached, may form morpholino; and R5 represents hydrogen.

6. A pharmaceutical composition comprising an effective amount of at
least one of the compounds according to claim 1 or pharmaceutically
acceptable salts thereof, and a pharmaceutically acceptable carrier.

7. A prostaglandin D synthase inhibitor comprising an effective amount of
a compound according to claim 1 or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier.

8. An agent for preventing or treating a disease associated with
prostaglandin D2 or a metabolite thereof, the agent comprising an
effective amount of a compound according to claim 1 or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. The agent according to claim 8, wherein the disease associated with
prostaglandin D2 or a metabolite is an allergic disease or inflammatory
disease.

10. A method for treating a disease associated with prostaglandin D2 or a
metabolite thereof, comprising administering to a patient in need of such
treatment an effective amount of a piperazine compound represented by
Formula (I) or a salt thereof ##STR00070## wherein X represents CH or
an N atom; R1 represents C1-6 alkyl; R2 represents
C1-6 alkyl that may have one or more substituents, C2-6 alkenyl
that may have one or more substituents, --(C═O)--N(R3)(R4),
or --(C═O)--OR5, R3 and R4 are the same or different,
and each represents hydrogen or C1-6 alkyl that may have one or more
substituents; or R3 and R4, taken together with a nitrogen atom
to which R3 and R4 are attached, may form a saturated
heterocyclic group; and R5 represents hydrogen or C1-6 alkyl
that may have one or more substituents or aralkyl.

11. The method according to claim 10, wherein the disease associated with
prostaglandin D2 or a metabolite thereof is an allergic disease or
inflammatory disease.

12. A piperazine compound represented by Formula I or a salt thereof for
use in the treatment of a disease associated with prostaglandin D2 or a
metabolite thereof ##STR00071## wherein X represents CH or an N atom;
R1 represents C1-6 alkyl; R2 represents C1-6 alkyl
that may have one or more substituents, C2-6 alkenyl that may have
one or more substituents, --(C═O)--N(R3)(R4), or
--(C═O)--OR5, R3 and R4 are the same or different, and
each represents hydrogen or C1-6 alkyl that may have one or more
substituents; or R3 and R4, taken together with a nitrogen atom
to which R3 and R4 are attached, may form a saturated
heterocyclic group; and R5 represents hydrogen or C1-6 alkyl
that may have one or more substituents or aralkyl.

13. Use of a piperazine compound represented by Formula I or a salt
thereof for treating a disease associated with prostaglandin D2 or a
metabolite thereof ##STR00072## wherein X represents CH or an N atom;
R1 represents C1-6 alkyl; R2 represents C1-6 alkyl
that may have one or more substituents, C2-6 alkenyl that may have
one or more substituents, --(C═O)--N(R3)(R4), or
--(C═O)--OR5, R3 and R4 are the same or different, and
each represents hydrogen or C1-6 alkyl that may have one or more
substituents; or R3 and R4, taken together with a nitrogen atom
to which R3 and R4 are attached, may form a saturated
heterocyclic group; and R5 represents hydrogen or C1-6 alkyl
that may have one or more substituents or aralkyl.

Description:

TECHNICAL FIELD

[0001] The present invention relates to a piperazine compound or a salt
thereof, and a pharmaceutical composition containing the piperazine
compound or salt thereof as an active ingredient, and in particular, to
an agent for preventing and/or treating allergic disease and inflammatory
disease due to its hematopoietic prostaglandin D synthase inhibiting
action.

BACKGROUND ART

[0002] Prostaglandin D2 (PGD2) is the inflammatory mediator produced and
released in the largest amounts by mast cells activated by the binding of
antigens with immunoglobulin E (NPL 1), and is considered to play an
important role in the elucidation of allergic reactions. PGD2 is detected
at a high concentration in an asthmatic's bronchoalveolar fluid (NPL 2),
and it was reported that bronchoconstriction was induced by PGD2
inhalation in asthmatic patients, but not in healthy subjects (NPL 3).

[0003] On the other hand, synthases that generate PGD2 are referred to as
prostaglandin D synthases (PGDS). Two different types, hematopoietic
prostaglandin D synthase and lipocalin-type prostaglandin D synthase, are
known to exist. PGD2 participates in the onset and exacerbation of
various diseases, including allergies, and in the regulatory mechanisms
of the body; therefore, pharmaceutical preparations that can ameliorate
excess production are considered to be very effective in the treatment of
various diseases.

[0004] Human hematopoietic prostaglandin D synthases (H-PGDS) are mainly
distributed throughout the placenta, lung, fetus liver, lymph node,
brain, heart, thymus, bone marrow, and spleen. Moreover, at the cellular
level, they are reported to be expressed in microglia in the brain,
megakaryocyte, and Langerhans cells in the skin; Kupffer cells in the
liver; macrophages; and many antigen-presenting cells such as dendritic
cells, mast cells, and Th2 cells.

[0005] From the fact that H-PGDS are highly expressed in mast cells or
inflammatory cells at nasal mucosa in allergic rhinitis, or nasal polyps
in chronic sinusitis, it is thought that PGD2 produced by H-PGDS plays an
important role in the onset and exacerbation of allergic diseases, such
as asthma, rhinosinusitis, dermatitis, and chronic obstructive pulmonary
disease (NPL4). Further, the expression of H-PGDS is confirmed in the
necrosed part of skeletal muscle, in which the expression of H-PGDS does
not generally occur (NPL5). For this reason, it is suggested that PGD2
produced by a hematopoietic prostaglandin D synthase participates in
diseases accompanied by tissue damage, such as muscular dystrophy,
amyotrophic lateral sclerosis, multiple sclerosis, ulcerative colitis,
rheumatoid arthritis, and chronic obstructive arterial disease.

[0006] Therefore, an H-PGDS inhibitor is expected to find application as a
pharmaceutical preparation that is useful as an agent for preventing
and/or treating diseases in which PGD2 produced by a hematopoietic
prostaglandin D synthase or a metabolite thereof participates, such as
allergic disease, inflammatory disease, muscle necrosis, and traumatic
brain injury.

[0007] There are some reports on an H-PGDS inhibitor (for example, PTL 1
and 2), and Patent Literature 3 discloses an H-PGDS inhibitor having a
structure similar to that of the compound of the present invention. In
addition, piperazine compounds have been widely studied as useful
pharmacological agents in addition to H-PGDS inhibitors.

[0020] The primary object of the present invention is to provide a novel
compound that exhibits, at a low dose, a high inhibitory effect on
prostaglandin D synthases; and, in particular, on H-PGDS.

[0021] Another ancillary object of the present invention is to provide a
medicine with few side effects and high safety, the medicine being
effective, due to its H-PGDS inhibiting action, in preventing and/or
treating diseases mediated by PGD2 generated by the synthase or
metabolite thereof.

Solution to Problem

[0022] The present inventors conducted extensive research on compounds
having an H-PGDS inhibiting action, and found that a novel piperazine
compound represented by Formula (I) has an extremely excellent inhibiting
action on H-PGDS. The inventors conducted further research, and have
accomplished the present invention.

[0023] The present invention provides a piperazine compound, a
pharmaceutical composition, a prostaglandin D synthase inhibitor, and an
agent for preventing or treating a disease associated with prostaglandin
D2 or a metabolite thereof, as described below.

Item 1.

[0024] A piperazine compound represented by Formula (I) or a salt thereof,

##STR00002##

wherein

[0025] X represents CH or an N atom;

[0026] R1 represents C1-6 alkyl;

[0027] R2 represents C1-6 alkyl that may have one or more
substituents, C2-6 alkenyl that may have one or more substituents,
--(C═O)--N(R3)(R4), or --(C═O)--OR5,

[0028] R3 and R4 are the same or different, and each represents
hydrogen or C1-6 alkyl that may have one or more substituents; or
R3 and R4, taken together with a nitrogen atom to which R3
and R4 are attached, may form a saturated heterocyclic group; and

[0029] R5 represents hydrogen or C1-6 alkyl that may have one or
more substituents or aralkyl.

Item 2.

[0030] The piperazine compound according to Item 1 or a salt thereof,
wherein

[0031] X represents CH or an N atom;

[0032] R1 represents methyl or ethyl;

[0033] R2 represents C1-3 alkyl that may have one or more
carbamoyl or unsaturated heterocyclic groups as substituents, propenyl
that may have one or more carbamoyl groups as substituents,
--(C═O)--N(R3)(R4), or --(C═O)--OR5;

[0034] one of R3 and R4 represents hydrogen and the other
represents C1-6 alkyl that may have one or more saturated or
unsaturated heterocyclic groups as substituents; or R3 and R4,
taken together with a nitrogen atom to which R3 and R4 are
attached, may form pyrrolidinyl, piperidinyl, piperazinyl, and
morpholino; and

[0035] R5 represents hydrogen, methyl, ethyl, tert-butyl, or benzyl.

Item 3.

[0036] The piperazine compound according to Item 1 or 2 or a salt thereof,
wherein

[0037] X represents CH or an N atom;

[0038] R1 represents methyl;

[0039] R2 represents C1-3 alkyl that may have any one of
morpholinocarbamoyl and triazolyl groups as a substituent,
--(C═O)--N(R3)(R4), or --(C═O)--OR5; and the
triazolyl may have one or two C1-6 alkyl as substituents;

[0040] one of R3 and R4 represents hydrogen and the other
represents C1-3 alkyl that may have one or more morpholino or
pyridyl groups as substituents; or R3 and R4, taken together
with a nitrogen atom to which R3 and R4 are attached, may form
morpholino; and

[0041] R5 represents hydrogen.

Item 4.

[0042] The piperazine compound according to any one of Items 1 to 3 or a
salt thereof, wherein

[0043] X represents CH;

[0044] R1 represents methyl;

[0045] R2 represents linear C1-3 alkyl that may have any one of
1,2,3-triazolyl, 1,2,4-triazolyl, and 3,5-dimethyl-1,2,4-triazolyl as a
substituent, --(C═O)--N(R3)(R4), or --(C═O)--OR5;

[0046] R3 and R4, taken together with a nitrogen atom to which
R3 and R4 are attached, may form morpholino; and

[0065] A pharmaceutical composition comprising an effective amount of at
least one of the compounds according to Items 1 to 5 or pharmaceutically
acceptable salts thereof, and a pharmaceutically acceptable carrier.

Item 7.

[0066] A prostaglandin D synthase inhibitor comprising an effective amount
of a compound according to any one of Items 1 to 5 or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable carrier.

Item 8.

[0067] An agent for preventing or treating a disease associated with
prostaglandin D2 or a metabolite thereof, the agent comprising an
effective amount of a compound according to any one of Items 1 to 5 or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.

Item 9.

[0068] The agent according to Item 8, wherein the disease associated with
prostaglandin D2 or a metabolite is an allergic disease or inflammatory
disease.

Item 10.

[0069] A method for treating a disease associated with prostaglandin D2 or
a metabolite thereof, comprising administering to a patient in need of
such treatment an effective amount of a piperazine compound represented
by Formula (I) or a salt thereof

##STR00003##

wherein

[0070] X represents CH or an N atom;

[0071] R1 represents C1-6 alkyl;

[0072] R2 represents C1-6 alkyl that may have one or more
substituents, C2-6 alkenyl that may have one or more substituents,
--(C═O)--N(R3)(R4), or --(C═O)--OR5,

[0073] R3 and R4 are the same or different, and each represents
hydrogen or C1-6 alkyl that may have one or more substituents; or
R3 and R4 taken together with a nitrogen atom to which R3
and R4 are attached, may form a saturated heterocyclic group; and

[0074] R5 represents hydrogen or C1-6 alkyl that may have one or
more substituents or aralkyl.

Item 11.

[0075] The method according to Item 10, wherein the disease associated
with prostaglandin D2 or a metabolite thereof is an allergic disease or
inflammatory disease.

Item 12.

[0076] A piperazine compound represented by Formula I or a salt thereof
for use in the treatment of a disease associated with prostaglandin D2 or
a metabolite thereof

##STR00004##

wherein

[0077] X represents CH or an N atom;

[0078] R1 represents C1-6 alkyl;

[0079] R2 represents C1-6 alkyl that may have one or more
substituents, C2-6 alkenyl that may have one or more substituents,
--(C═O)--N(R3)(R4), or --(C═O)--OR5,

[0080] R3 and R4 are the same or different, and each represents
hydrogen or C1-6 alkyl that may have one or more substituents; or
R3 and R4 taken together with a nitrogen atom to which R3
and R4 are attached, may form a saturated heterocyclic group; and

[0081] R5 represents hydrogen or C1-6 alkyl that may have one or
more substituents or aralkyl.

Item 13.

[0082] Use of a piperazine compound represented by Formula I or a salt
thereof for treating a disease associated with prostaglandin D2 or a
metabolite thereof

##STR00005##

wherein

[0083] X represents CH or an N atom;

[0084] R1 represents C1-6 alkyl;

[0085] R2 represents C1-6 alkyl that may have one or more
substituents, C2-6 alkenyl that may have one or more substituents,
--(C═O)--N(R3)(R4), or --(C═O)--OR5,

[0086] R3 and R4 are the same or different, and each represents
hydrogen or C1-6 alkyl that may have one or more substituents; or
R3 and R4 taken together with a nitrogen atom to which R3
and R4 are attached, may form a saturated heterocyclic group; and

[0087] R5 represents hydrogen or C1-6 alkyl that may have one or
more substituents or aralkyl.

Advantageous Effects of Invention

[0088] The present invention provides a novel piperazine compound
represented by the above Formula (I) or a salt thereof, which is useful
as a prostaglandin D synthase inhibitor; and, in particular, as an H-PGDS
inhibitor.

[0089] The piperazine compound or a salt thereof according to the present
invention has excellent H-PGDS inhibitory activity in vitro. Further, it
is revealed that the piperazine compound or a salt thereof exhibits PGD2
production inhibiting action in a nasal cavity washing liquid in guinea
pigs with antigen-induced rhinitis, and that the piperazine compound or a
salt thereof has an excellent nasal congestion improving action.

[0090] Thus, based on its excellent H-PGDS inhibitory activity, the
piperazine compound or a salt thereof according to the present invention
is useful as an agent for preventing and/or treating a disease associated
with PGD2 or a metabolite thereof, such as an allergic disease and
inflammatory disease, and is expected to have other useful effects.

DESCRIPTION OF EMBODIMENTS

[0091] The piperazine compound of the present invention is a piperazine
compound represented by Formula (I) or a salt thereof,

##STR00006##

wherein

[0092] X represents CH or an N atom;

[0093] R1 represents C1-6 alkyl;

[0094] R2 represents C1-6 alkyl that may have one or more
substituents, C2-6 alkenyl that may have one or more substituents,
--(C═O)--N(R3)(R4), or --(C═O)--OR5;

[0095] R3 and R4 are the same or different, and each represents
hydrogen or C1-6 alkyl that may have one or more substituents; or
R3 and R4, taken together with a nitrogen atom to which R3
and R4 are attached, may form a saturated heterocyclic group; and

[0096] R5 represents hydrogen or C1-6 alkyl that may have one or
more substituents or aralkyl.

[0097] The piperazine compound of the present invention, which is
represented by Formula (I), is a compound having both
(N-alkylpyrrol-2-yl)carbonyl and (piperidin-4-yl)aminocarbonyl, and is a
novel compound not specifically disclosed in the aforementioned
literature.

[0098] For example, Patent Literature 3 (WO2008/122787) discloses a wide
range of piperazine compounds that inhibit H-PGDS; however, Patent
Literature 3 is different from the present invention in that the compound
of the present invention has (piperidin-4-yl)aminocarbonyl. In addition,
Patent Literature 3 is completely silent about a piperazine compound
having (N-alkylpyrrol-2-yl)carbonyl, which is contained in the compound
of the present invention. Further, as shown in the Test Examples
described below, the compounds demonstrated in the Examples (Reference
Examples 12 to 17) of Patent Literature 3 do not exhibit PGD2 production
inhibiting action in a nasal cavity washing liquid in guinea pigs with
antigen-induced rhinitis.

[0099] Patent Literature 4 (WO2007/054623) discloses as an inhibitor of
hedgehog signaling a piperazine compound having a furyl carbonyl
piperazine structure; however, Patent Literature 4 is different from the
present invention in that (N-alkylpyrrol-2-yl)carbonyl used in the
compound of the present invention is limited to furyl carbonyl. Further,
Patent Literature 4 is completely silent about H-PGDS inhibiting action.

[0100] Patent Literature 5 (WO99/007672) discloses a furyl carbonyl
piperazine compound, a benzoylpiperazine compound, etc., as a compound
that interacts with a potassium channel. However, Patent Literature 5
does not disclose a compound having (N-alkylpyrrol-2-yl)carbonyl as in
the present compound, and is completely silent about H-PGDS inhibiting
action.

[0101] As shown in the Test Examples below, a piperazine compound having
no (N-alkylpyrrol-2-yl)carbonyl exhibits almost no H-PGDS inhibiting
action.

[0103] In the substituents, examples of halogen include chlorine, bromine,
fluorine, and iodine.

[0104] In the substituents, alkyl or halogenoalkyl is preferably a
straight or branched C1-6 or C1-4alkyl group or a group in
which one to all of the hydrogen atoms of the alkyl group is substituted
with halogen described above. Examples thereof include alkyl groups such
as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, and hexyl; and halogenoalkyl groups such as
trifluoromethyl.

[0105] In the substituents, cycloalkyl is preferably a C3-7
cycloalkyl group, and examples thereof include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, and cycloheptyl.

[0106] In the substituents, cycloalkyl-alkyl is preferably a C1-6
alkyl group substituted with a C3-7 cycloalkyl group, and examples
thereof include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl,
cyclopentylmethyl, and cyclohexylmethyl.

[0107] In the substituents, aralkyl is preferably a straight or branched
C1-6 alkyl group substituted with a C6-14 aromatic hydrocarbon
group, and examples thereof include benzyl, phenylethyl, phenylpropyl,
naphthylmethyl, and naphthylethyl.

[0108] In the substituents, alkenyl is preferably a C2-6 alkenyl
group containing a carbon-carbon double bond, and examples thereof
include vinyl, allyl, methylvinyl, propenyl, butenyl, pentenyl, and
hexenyl.

[0109] In the substituents, alkynyl is preferably a C2-6 alkynyl
group containing a carbon-carbon triple bond, and examples thereof
include ethynyl and propargyl.

[0111] In the substituents, cycloalkoxy is preferably a C2-7
cycloalkoxy group, and examples thereof include cyclopropoxy,
cyclobutoxy, cyclopenthyloxy, cyclohexyloxy, and cycloheptyloxy.

[0112] In the substituents, cycloalkyl-alkoxy is preferably a C1-6
alkoxy group substituted with a C3-7 cycloalkyl group, and examples
thereof include cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy,
cyclopentylmethoxy, and cyclohexylmethoxy.

[0113] In the substituents, aralkyloxy is preferably an oxy group having
the aforementioned aralkyl group, and examples thereof include benzyloxy,
phenethyloxy, phenylpropyloxy, naphthylmethyloxy, and naphthylethyloxy.

[0115] In the substituents, cycloalkyl-alkylthio is preferably a C1-6
alkylthio group substituted with a C3-7 cycloalkyl group, and
examples thereof include cyclopropylmethylthio, cyclopropylethylthio,
cyclobutylmethylthio, cyclopentylmethylthio, and cyclohexylmethylthio.

[0116] In the substituents, mono- or di-alkylamino is an amino group mono-
or di-substituted with the aforementioned straight or branched C1-6
alkyl group, and examples thereof include methylamino, dimethylamino,
ethylamino, diethylamino, and methylethylamino.

[0117] In the substituents, cycloalkyl-alkylamino is an alkylamino group
substituted with the aforementioned cycloalkyl group, and examples
thereof include cyclopropylmethylamino, cyclobutylmethylamino, and
cyclopentylmethylamino.

[0118] In the substituents, acyl is a straight or branched C1-6 acyl
group or benzoyl group, and examples thereof include formyl, acetyl,
propionyl, n-butyryl, isobutyryl, valeryl, isovaleryl, and pivaloyl.

[0119] In the substituents, acyloxy is a straight or branched C1-6
alkanoyloxy group or benzoyloxy group, and examples thereof include
formyloxy, acetoxy, propionyloxy, n-butyryloxy, isobutyryloxy,
valeryloxy, isovaleryloxy, and pivaloyloxy.

[0120] In the substituents, alkoxycarbonyl is a carbonyl group substituted
with the aforementioned alkoxy group, and examples thereof include
methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,
1-methylpropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl,
tert-butoxycarbonyl, 2-methyl-butoxycarbonyl, neopentyloxycarbonyl, and
pentan-2-yloxycarbonyl.

[0121] In the substituents, aralkyloxycarbonyl is preferably a carbonyl
group substituted with the aforementioned aralkyloxy group, and examples
thereof include benzyloxycarbonyl, phenethyloxycarbonyl,
phenylpropyloxycarbonyl, naphthlmethyloxycarbonyl, and
naphthylethyloxycarbonyl.

[0122] In the substituents, examples of carbamoyl include --CONH2,
(mono- or di-alkyl)carbamoyl, (mono- or di-aryl)carbamoyl,
(N-alkyl-N-aryl) carbamoyl, pyrrolidinocarbamoyl, piperidinocarbamoyl,
piperazinocarbamoyl, and morpholinocarbamoyl.

[0124] In the substituents, aromatic hydrocarbon is preferably a
C6-14 aromatic hydrocarbon group, and examples thereof include
phenyl and naphthyl. In the substituents, saturated heterocycloxy group
is a monocyclic saturated heterocyclic group having any one of oxygen,
nitrogen, and sulfur in an amount of one or two, and examples thereof
include oxy groups having pyrrolidinyl, piperidinyl, piperazinyl,
hexamethyleneimino, morpholino, thiomorpholino, homopiperazinyl,
tetrahydrofuranyl, tetrahydropyranyl, etc., such as tetrahydrofuranyloxy
and tetrahydropyranyloxy.

[0125] "C1-6 alkyl" represented by R1 in Formula (I) is a
straight or branched C1-6 alkyl group, and examples thereof include
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,
n-pentyl, and n-hexyl. Of these, methyl and ethyl are preferable, and
methyl is more preferable.

[0126] Examples of the "C1-6 alkyl" of the "C1-6 alkyl that may
have one or more substituents" represented by R2 in Formula (I)
include C1-6 alkyl represented by R1. Of these, C1-3 alkyl
is preferable, and straight C1-3 alkyl such as methyl, ethyl, and
n-propyl are more preferable.

[0127] Examples of the "substituents" of the "C1-6 alkyl that may
have one or more substituents" represented by R2 include the
above-mentioned substituents. Carbamoyl or unsaturated heterocyclic
groups are preferable; morpholinocarbamoyl and triazolyl are more
preferable; and morpholinocarbamoyl, 1,2,3-triazolyl, and 1,2,4-triazolyl
are particularly preferable. The unsubstituted heterocyclic groups may
have substituents. A preferable substituent is methyl, and the number of
substituents is 1 or 2.

[0128] Particularly preferable examples of "C1-6 alkyl that may have
one or more substituents" represented by R2 include
morpholinocarbamoyl-ethyl, 1,2,3-triazolyl-ethyl, 1,2,3-triazolyl-propyl,
1,2,4-triazolyl-propyl, 3,5-dimethyl-1,2,4-triazolyl-ethyl, and
3,5-dimethyl-1,2,4-triazolyl-propyl.

[0129] Examples of the "C2-6 alkenyl" of the "C2-6 alkenyl that
may have one or more substituents" represented by R2 include
C2-6 alkenyl described above. Of these, vinyl is preferable.

[0130] Examples of the "substituents" of the "C2-6 alkenyl that may
have one or more substituents" represented by R2 include the
above-mentioned substituents. Carbamoyl that may have one or more
substituents is preferable; and morpholinocarbamoyl is more preferable.

[0131] Examples of the "C1-6 alkyl" of the "C1-6 alkyl that may
have one or more substituents" represented by R3 and R4 in
Formula (I) include C1-6 alkyl represented by R1. Of these,
C1-3 alkyl is preferable; and methyl or ethyl is more preferable.

[0132] Examples of the "substituents" of the "C1-6 alkyl that may
have one or more substituents" represented by R3 and R4 include
the above-mentioned substituents. Of these, saturated or unsaturated
heterocyclic groups are preferable; morpholino or pyridyl is more
preferable.

[0133] It is preferred that one of R3 and R4 is hydrogen and the
other is C1-6 alkyl that may have one or more substituents; it is
particularly preferred that one of R3 and R4 is hydrogen and
the other is C1-3 alkyl that has morpholino or pyridyl.

[0134] Examples of the "saturated heterocyclic group" that may be formed
by R3 and R4 in Formula (I) together with a nitrogen atom to
which R3 and R4 are attached, include pyrrolidinyl,
piperidinyl, piperazinyl, and morpholino; and pyrrolidinyl, piperidinyl,
and morpholino are preferable.

[0135] Preferable examples of the "C1-6 alkyl that may have one or
more substituents" represented by R5 in Formula (I) include methyl,
ethyl, tert-butyl, and benzyl. R5 is preferably hydrogen.

[0136] The piperazine compound of the present invention can be produced
according to the following Reaction Schemes 1 to 7.

Method for Producing the Compound of the Present Invention

[0137] A representative method for producing the compound represented by
Formula (I) is described. [Method 1]

##STR00007##

[0138] In the above Reaction Scheme 1, X, R1 and R2 are the same
as above, and R represents a protective group of amino group or hydrogen.

First Step

[0139] The amide compound shown in Formula (2) can be obtained by
condensing the piperazine compound shown in Formula (1a) or a salt
thereof with the pyrrolecarboxylic acid compound shown in Formula (1b) or
an active species thereof by an ordinary method.

[0140] Examples of the active species of compound (1b) include ordinary
esters such as methyl esters; acid halides such as acid chlorides; active
esters with N-hydroxybenzotriazole, etc.; symmetrical acid anhydrides;
and mixed acid anhydrides with alkyl carbonic acids, etc.

[0141] When the compound (1b) is reacted with a free acid, or when an
active ester or acid halide is reacted without being isolated, a
condensation agent such as 1-ethyl-3-(3-dimethylamino propyl)carbodiimide
hydrochloride and
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride is
preferably used.

[0142] When 0.5 to 10 moles, and preferably 0.8 to 2 moles of the
carboxylic acid compound shown in Formula (1b) or an active species
thereof is used relative to 1 mole of the piperazine compound shown in
Formula (1a) or a salt thereof, the amount of the condensation agent is
0.5 to 20 moles, and preferably 0.8 to 3 moles relative to 1 mole of the
piperazine compound shown in Formula (1a) or a salt thereof.

[0143] Although dependent on the active species or condensation agent
used, the reaction is normally carried out in a solvent which is inactive
to the reaction at -20 to 150° C., and preferably at 0 to
100° C. Examples of such a solvent include halogenated
hydrocarbons such as dichloromethane and chloroform; aromatic
hydrocarbons such as toluene; ethers such as tetrahydrofuran; esters such
as ethyl acetate; alcohols such as methanol and ethanol; water;
acetonitrile; N,N-dimethylformamide; N,N-dimethylacetamide;
dimethylsulfoxide; and pyridine. The reaction time is about 1 to 24
hours.

[0144] The reaction may proceed smoothly if it is carried out in the
presence of 0.5 to 20 moles, and preferably 0.8 to 5 moles of a base such
as triethylamine, diisopropylethylamine, N-methylmorpholine,
N,N-dimethylaniline, 4-(N,N-dimethylamino)pyridine, and pyridine,
relative to 1 mole of the piperazine compound shown in Formula (1a) or a
salt thereof.

Second Step

[0145] In the second step, the protective group R of amino group in the
amide compound shown in Formula (2) is deprotected by an ordinary, known
method, and the result and the amine compound shown in Formula (1c) or an
active species thereof are condensed by an ordinary method to obtain the
compound shown in Formula (I).

[0146] Deprotection can be carried out under acidic conditions when the
protective group R is formyl, tert-butoxycarbonyl, or the like; and
deprotection can be performed by, for example, a catalytic reduction
method when the protective group R is benzyl, benzyloxycarbonyl, or the
like.

[0147] In the condensation, it is preferable to use an active species
having a leaving group that is prepared by reacting the amine compound
shown in Formula (1c) or a salt thereof with triphosgene,
1,1'-carbonyldiimidazole (CDI), phenyl chloroformate, 4-nitrophenyl
chloroformate, ethyl chloroformate, or the like, in a solvent that is
inactive to the reaction, such as dichloromethane, chloroform,
tetrahydrofuran, acetonitrile, ethyl acetate, or N,N-dimethylacetamide,
at -50 to 150° C., and preferably -20 to 100° C., in the
presence or absence of an organic base such as triethylamine or pyridine.
The reaction time is about 1 to 24 hours.

[0148] The active species of Formula (1c) may have a leaving group. The
active species may be used for reaction after isolation, or may be
prepared in a reaction system and used without isolation. Examples of the
leaving group include chlorine, imidazolyl, phenoxy, nitrophenoxy, and
ethoxy.

[0149] Examples of the salts of the amine compound shown in Formula (2)
include acid addition salts with inorganic acids, such as hydrochloric
acid, hydrobromic acid, and sulfuric acid; or with organic acids, such as
carbonic acid and methanesulfonic acid.

[0150] When 0.5 to 10 moles, and preferably 0.8 to 2 moles, of the amine
compound shown in Formula (2) or a salt thereof is used relative to 1
mole of the amine compound shown in Formula (1c) or an active species
thereof, the amount of the condensation agent is 0.5 to 20 moles, and
preferably 0.8 to 3 moles, relative to 1 mole of the amine compound shown
in Formula (1c) or a salt thereof.

[0151] Although dependent on the active species or condensation agent
used, the reaction is normally carried out in a solvent that is inactive
to the reaction at -50 to 150° C., and preferably at -20 to
100° C. Examples of the solvent include halogenated hydrocarbons
such as dichloromethane and chloroform; aromatic hydrocarbons such as
toluene; ethers such as tetrahydrofuran; esters such as ethyl acetate;
alcohols such as methanol and ethanol; water; acetonitrile;
N,N-dimethylformamide; N,N-dimethylacetamide; dimethylsulfoxide; and
pyridine.

[0152] The reaction may proceed smoothly if it is carried out in the
presence of about 0.5 to 20 moles, and preferably 0.8 to 5 moles, of a
base such as triethylamine, diisopropylethylamine, N-methylmorpholine,
N,N-dimethylaniline, 4-(N,N-dimethylamino)pyridine, and pyridine,
relative to 1 mole of the amine compound shown in Formula (1c) or an
active species thereof.

[0153] Note that the compound of the present invention can also be
produced by transposing the first step and the second step, and R2
can be converted according to an ordinary, known method if required. The
piperazine compound shown in Formula (1a) or a salt thereof, the
pyrrolecarboxylic acid compound shown in Formula (1b) or an active
species thereof, and the amine compound shown in Formula (1c) or a salt
thereof are readily available, or can be produced in accordance with a
known method.

[0154] Next, the production method of the compound (1c) in the
aforementioned Reaction Scheme is shown in Reaction Schemes 2, 3, 4, and
5.

##STR00008##

[0155] In the above Reaction Scheme 2, X and R are the same as above,
R6 is the same as R5 or a silyl protective group such as
tert-butyldimethylsilyl, and R7 and R8 are the same as the
"substituents" of the "C1-6 alkyl groups that may have one or more
substituents" represented by R2. R7 and R8 particularly
represent substituted or unsubstituted heterocyclic groups; and Y1,
Y2 and Y3 represent leaving functional groups.

First Step

[0156] Any leaving functional group can be used as Y2 of the compound
(2b) in the first step. Examples thereof include halogen such as fluorine
and chlorine, methanesulfonyloxy, and p-toluenesulfonyloxy.

[0157] In a suitable solvent, using 0.5 to 10 moles, and preferably 0.8 to
2 moles, of the piperidine compound shown in Formula (2a) or a salt
thereof relative to 1 mole of the compound shown in Formula (2b),
reaction is conducted in the presence of 0.5 to 10 moles, and preferably
0.8 to 3 moles, of a base relative to 1 mole of the compound shown in
Formula (2b), at -20 to 180° C., and preferably at 0 to
150° C., for about 1 to 24 hours, thereby obtaining the ester
group-containing compound shown in Formula (2c).

[0158] Any reaction solvents can be used as long as they do not adversely
affect the reaction. Examples thereof include halogenated hydrocarbons
such as dichloromethane and chloroform; aromatic hydrocarbons such as
toluene; ethers such as tetrahydrofuran; esters such as ethyl acetate;
alcohols such as methanol and ethanol; water; acetonitrile;
N,N-dimethylformamide; N,N-dimethylacetamide; N-methylpyrrolidone;
dimethylsulfoxide; and pyridine. The solvents can be used singly, or in
combination.

[0160] In the case where R is hydrogen, in a suitable solvent, using 0.5
to 10 moles, and preferably 0.8 to 2 moles, of an amino group protecting
reagent relative to 1 mole of the compound shown in Formula (2c),
reaction is conducted in the presence of 0.5 to 10 moles, and preferably
0.8 to 3 moles, of a base relative to 1 mole of the compound shown in
Formula (2c), at -20 to 180° C., and preferably at 0 to
150° C., for about 1 to 24 hours, thereby obtaining the compound
shown in Formula (2c), which has a protected amino group.

[0161] Any reaction solvents can be used as long as they do not adversely
affect the reaction. Examples thereof include halogenated hydrocarbons
such as dichloromethane and chloroform; aromatic hydrocarbons such as
toluene; ethers such as tetrahydrofuran; esters such as ethyl acetate;
alcohols such as methanol and ethanol; water; acetonitrile;
N,N-dimethylformamide; N,N-dimethylacetamide; N-methylpyrrolidone;
dimethylsulfoxide; and pyridine. The solvents can be used singly, or in
combination.

[0164] In this step, in a suitable solvent, the ester group-containing
compound shown in Formula (2c) is reacted in the presence of 0.2 to 10
moles, and preferably 0.5 to 5 moles, of a reducing agent relative to 1
mole of the compound shown in Formula (2c), at -80 to 100° C., and
preferably at -50 to 30° C., for about 1 to 24 hours, thereby
obtaining the hydroxyl group-containing compound shown in Formula (2d).

[0165] Any reaction solvents can be used as long as they do not adversely
affect the reaction. Examples thereof include aliphatic hydrocarbons such
as n-hexane, aromatic hydrocarbons such as toluene, ethers such as
tetrahydrofuran, alcohols such as methanol and ethanol, and water. The
solvents can be used singly, or in combination.

[0167] In a suitable solvent, using 0.5 to 10 moles, and preferably 0.8 to
2 moles, of the leaving functional group-containing compound shown in
Formula (2e) relative to 1 mole of the hydroxyl group-containing compound
shown in Formula (2d), reaction is conducted in the presence or absence
of 0.5 to 10 moles, and preferably 0.8 to 3 moles, of a base relative to
1 mole of the compound shown in Formula (2d), at -20 to 180° C.,
and preferably at 0 to 150° C., for about 1 to 24 hours, thereby
obtaining the compound shown in Formula (2f).

[0168] Any solvents can be used as long as they do not adversely affect
the reaction. Examples of suitable solvents include halogenated
hydrocarbons such as dichloromethane and chloroform; aromatic
hydrocarbons such as toluene; ethers such as tetrahydrofuran; esters such
as ethyl acetate; alcohols such as methanol and ethanol; water;
acetonitrile; N,N-dimethylformamide; N,N-dimethylacetamide;
N-methylpyrrolidone; dimethylsulfoxide; and pyridine. The solvents can be
used singly, or in combination.

[0171] In a suitable solvent, using 0.5 to 10 moles, and preferably 0.8 to
3 moles, of the amine compound shown in Formula (2g) or a salt thereof
relative to 1 mole of the compound shown in Formula (2f), reaction is
conducted in the presence or absence of 0.5 to 10 moles, and preferably
0.8 to 3 moles, of a base relative to 1 mole of the compound shown in
Formula (2f), at -20 to 180° C., and preferably at 0 to
150° C., for 1 to 24 hours, thereby obtaining the compound shown
in Formula (2h).

[0172] Any solvents can be used, as long as they do not adversely affect
the reaction. Examples of suitable solvents include halogenated
hydrocarbons such as dichloromethane and chloroform; aromatic
hydrocarbons such as toluene; ethers such as tetrahydrofuran; esters such
as ethyl acetate; acetonitrile; N,N-dimethylformamide;
N,N-dimethylacetamide; N-methylpyrrolidone; dimethylsulfoxide; and
pyridine. The solvents can be used singly, or in combination.

[0173] Examples of usable bases include inorganic bases such as sodium
hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, and
sodium hydride; and organic bases such as pyridine,
4-(N,N-dimethylamino)pyridine, triethylamine, diisopropylethylamine,
1,8-diazabicyclo[5.4.0]undec-7-en, and potassium tert-butoxide. As a
base, an excess of the amine compound shown in Formula (2g) may be used.

Fifth Step

[0174] In the fifth step, the protective group R of amino group in the
compound shown in Formula (2h) is deprotected by an ordinary, known
method to obtain the compound shown in Formula (2i).

[0175] Deprotection can be carried out under acidic conditions when the
protective group R is formyl or tert-butoxycarbonyl; and deprotection can
be performed by, for example, a catalytic reduction method when the
protective group R is benzyl, benzyloxycarbonyl, or the like.

[0176] The compounds (2a), (2b), (2e), and (2g) used in Reaction Scheme 2
are readily available, or can be produced in accordance with a known
method.

##STR00009## ##STR00010##

[0177] In the above Reaction Scheme 3, W is a protective group of hydroxyl
group, and R, R6, R7, R8, X, Y1, Y2 and Y3
are the same as above.

First Step

[0178] In this step, the ester group-containing compound represented by
Formula (3c) can be obtained in the same manner as in the first step of
Reaction Scheme 2.

Second Step

[0179] In this step, the hydroxyl group-containing compound represented by
Formula (3d) can be obtained in the same manner as in the second step of
Reaction Scheme 2.

Third Step

[0180] In this step, the hydroxyl group-containing compound represented by
Formula (3d) is oxidized by an ordinary, known method to obtain the
aldehyde group-containing compound (3e).

[0181] In a suitable solvent, reaction is conducted in the presence of 0.8
to 100 moles, and preferably 1 to 30 moles, of an oxidizing agent
relative to 1 mole of the compound shown in Formula (3d), at -80 to
180° C., and preferably at -50 to 150° C., for about 1 to 3
days, thereby obtaining the aldehyde group-containing compound shown in
Formula (3e).

[0182] Any solvents can be used, as long as they do not adversely affect
the reaction. Examples of suitable solvents include halogenated
hydrocarbons such as dichloromethane, chloroform, and dichloroethane;
aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran;
and dimethyl sulfoxide. The solvents can be used singly, or in
combination.

[0184] In a suitable solvent, using 0.8 to 10 moles, and preferably 1 to 8
moles, of the Wittig reagent shown in Formula (3f) relative to 1 mole of
the aldehyde compound shown in Formula (3e), reaction is conducted in the
presence of 0.5 to 10 moles, and preferably 0.8 to 5 moles, of a base
relative to 1 mole of the compound shown in Formula (3e), at -20 to
150° C., and preferably at 0 to 80° C., for about 1 to 24
hours, thereby obtaining the compound shown in Formula (3g).

[0185] Any solvents can be used, as long as they do not adversely affect
the reaction. Examples of suitable solvents include aliphatic
hydrocarbons such as n-hexane, aromatic hydrocarbons such as toluene, and
ethers such as tetrahydrofuran. The solvents can be used singly, or in
combination.

[0186] Examples of the protective group W of hydroxyl group in the Wittig
reagent shown in Formula (3f) include methyl, methoxymethyl,
tetrahydropyranyl, and tert-butyldimethylsilyl.

[0188] After the protective group of hydroxyl group in the compound shown
in Formula (3g) is deprotected in a suitable solvent under acidic
conditions, the aldehyde group-containing compound is reacted in a
suitable solvent in the presence of 0.2 to 10 moles, and preferably 0.5
to 5 moles, of a reducing agent relative to 1 mole of the compound shown
in Formula (3g), at -80 to 100° C., and preferably at -50 to
30° C., for about 1 to 24 hours, thereby obtaining the hydroxyl
group-containing compound shown in Formula (3h).

[0189] Any reaction solvents can be used, as long as they do not adversely
affect the reaction. Examples thereof include aliphatic hydrocarbons such
as n-hexane, aromatic hydrocarbons such as toluene, ethers such as
tetrahydrofuran, alcohols such as methanol and ethanol, and water. The
solvents can be used singly, or in combination.

[0191] In this step, the leaving group-containing compound represented by
Formula (3j) can be obtained in the same manner as in the third step of
Reaction Scheme 2.

Seventh Step

[0192] In this step, the amino group-containing compound represented by
Formula (31) can be obtained in the same manner as in the fourth step of
Reaction Scheme 2.

Eighth Step

[0193] In this step, the amino group-containing compound represented by
Formula (3m) can be obtained in the same manner as in the fifth step of
Reaction Scheme 2.

[0194] The compounds (3a), (3b), (3f), (3i), and (3k) used in Reaction
Scheme 3 are readily available, or can be produced in accordance with a
known method.

##STR00011## ##STR00012##

[0195] In the above Reaction Scheme 4, R9 is a protective group of
ester group, and R, R6, R7, R8, X, Y1, Y2, and
Y3 are the same as above. Z is
CH2P+R103Y4-, CH═PR113, or
CH2P(O)(OR12)2. R10, R11, and R12 are lower
alkyl such as methyl, ethyl, or butyl, or an aromatic hydrocarbon group
such as phenyl; and Y4 is halogen such as chlorine or bromine.

First Step

[0196] In this step, the ester group-containing compound represented by
Formula (4c) can be obtained in the same manner as in the first step of
Reaction Scheme 2.

Second Step

[0197] In this step, the hydroxyl group-containing compound represented by
Formula (4d) can be obtained in the same manner as in the second step of
Reaction Scheme 2.

Third Step

[0198] In this step, the aldehyde group-containing compound represented by
Formula (4e) can be obtained in the same manner as in the third step of
Reaction Scheme 3.

Fourth Step

[0199] In a suitable solvent, using 0.8 to 10 moles, and preferably 1 to 8
moles, of the Wittig reagent or Horner-Emmons reagent shown in Formula
(4f) relative to 1 mole of the aldehyde compound shown in Formula (4e),
reaction is conducted in the presence or absence of 0.5 to 10 moles, and
preferably 0.8 to 5 moles, of a base relative to 1 mole of the compound
shown in Formula (4e), at -20 to 150° C., and preferably at 0 to
120° C., for about 1 to 24 hours, thereby obtaining an
α,β-unsaturated ester group-containing compound.

[0200] Any solvents can be used, as long as they do not adversely affect
the reaction. Examples of suitable solvents include aliphatic
hydrocarbons such as n-hexane, aromatic hydrocarbons such as toluene, and
ethers such as tetrahydrofuran. The solvents can be used singly, or in
combination.

[0201] Examples of the protective group (R9) of ester group in the
Wittig reagent or Horner-Emmons reagent shown in (4f) include methyl,
ethyl, tert-butyl, tert-butyldimethylsilyl, and benzyl.

[0203] In ethers such as tetrahydrofuran, esters such as ethyl acetate,
alcohols such as methanol and ethanol, organic acids such as formic acid
and acetic acid, or a mixture of solvents thereof, hydrogen gas is
reacted under ordinary pressure or high pressure in the presence of 0.001
to 1 mole, and preferably 0.01 to 0.3 moles, of a reduction catalyst such
as carbon-supported palladium, platinum oxide, and Raney nickel, relative
to 1 mole of the compound shown in Formula (4e), at 0 to 120° C.,
and preferably 20 to 100° C., or using 0.5 to 20 moles, and
preferably 1 to 10 moles, of formic acid, ammonium formate, cyclohexene,
etc., relative to 1 mole of the compound shown in Formula (4e) as a
hydrogen source in place of hydrogen gas, reaction is conducted for about
1 to 3 days, thereby obtaining the ester group-containing compound shown
in Formula (4g).

Fifth Step

[0204] In this step, the hydroxyl group-containing compound represented by
Formula (4h) can be obtained in the same manner as in the second step of
Reaction Scheme 1.

Sixth Step

[0205] In this step, the leaving group-containing compound represented by
Formula (4j) can be obtained in the same manner as in the third step of
Reaction Scheme 2.

Seventh Step

[0206] In this step, the amino group-containing compound represented by
Formula (4l) can be obtained in the same manner as in the fourth step of
Reaction Scheme 2.

Eighth Step

[0207] In this step, the amino group-containing compound represented by
Formula (4m) can be obtained in the same manner as in the fifth step of
Reaction Scheme 2.

[0208] The compounds (4a), (4b), (4f), (4i) and (4k) used in Reaction
Scheme 4 are readily available, or can be produced in accordance with a
known method.

##STR00013## ##STR00014##

[0209] In the above Reaction Scheme 5, V1 is --CH═CH-- or
--CH2CH2--, and R, R6, R7, R8, R9, X,
Y1 and Z are the same as above.

First Step

[0210] In this step, the ester group-containing compound represented by
Formula (5c) can be obtained in the same manner as in the first step of
Reaction Scheme 2.

Second Step

[0211] In this step, the hydroxyl group-containing compound represented by
Formula (5d) can be obtained in the same manner as in the second step of
Reaction Scheme 2.

Third Step

[0212] In this step, the aldehyde group-containing compound represented by
Formula (5e) can be obtained in the same manner as in the third step of
Reaction Scheme 3.

Fourth Step

[0213] In a suitable solvent, using 0.8 to 10 moles, and preferably 1 to 8
moles, of the Wittig reagent or Horner-Emmons reagent shown in Formula
(5f) relative to 1 mole of the aldehyde compound shown in Formula (5e),
reaction is conducted in the presence or absence of 0.5 to 10 moles, and
preferably 0.8 to 5 moles, of a base relative to 1 mole of the compound
shown in Formula (5e), at -20 to 150° C., and preferably at 0 to
120° C., for about 1 to 24 hours, thereby obtaining the
α,β-unsaturated ester group-containing compound shown in
Formula (5g).

[0214] Any solvents can be used, as long as they do not adversely affect
the reaction. Examples of suitable solvents include aliphatic
hydrocarbons such as n-hexane, aromatic hydrocarbons such as toluene, and
ethers such as tetrahydrofuran. The solvents can be used singly, or in
combination.

[0215] Examples of the protective group (R9) of ester group in the
Wittig reagent or Horner-Emmons reagent shown in (5f) include methyl,
ethyl, tert-butyl, tert-butyldimethylsilyl, and benzyl.

[0217] In this step, the ester group of the ester group-containing
compound shown in Formula (5g) is deprotected by an ordinary, known
method to obtain the carboxylic acid compound shown in Formula (5h).

Sixth Step

[0218] In this step, condensation reaction with the amine compound shown
in Formula (5i) or a salt thereof is conducted in the same manner as in
the first step of Reaction Scheme 1 to obtain the amide compound shown in
Formula (5j).

Seventh Step

[0219] In this step, when V1 in the compound shown in Formula (5k) is
--CH═CH--, the amino group-containing compound shown in Formula (5k)
can be obtained in the same manner as in the fifth step of Reaction
Scheme 2.

[0220] In this step, when V1 in the compound shown in Formula (5k) is
--CH2CH2--, in ethers such as tetrahydrofuran, esters such as
ethyl acetate, alcohols such as methanol and ethanol, organic acid such
as formic acid and acetic acid, or a mixture of solvents thereof,
hydrogen gas is reacted under ordinary pressure or high pressure in the
presence of 0.001 to 1 mole, and preferably 0.01 to 0.3 moles, of a
reduction catalyst such as carbon-supported palladium, platinum oxide,
and Raney nickel, relative to 1 mole of the compound shown in Formula
(5j), at 0 to 120° C., and preferably 20 to 100° C., or
using 0.5 to 20 moles, and preferably 1 to 10 moles, of formic acid,
ammonium formate, cyclohexene, etc. relative to 1 mole of the compound
shown in Formula (5j) as a hydrogen source in place of hydrogen gas,
reaction is conducted for about 1 to 3 days, and then, the amino
group-containing compound shown in Formula (5k) can be obtained in the
same manner as in the fifth step of Reaction Scheme 2.

[0221] The compounds (5a), (5b), (5f), and (5i) used in Reaction Scheme 5
are readily available, or can be produced in accordance with a known
method.

[0222] The compounds (3e), (4e), and (5e) used in Reaction Schemes 3 to 5
can also be produced as shown in Reaction Scheme 6 described below.

##STR00015##

[0223] In the above Reaction Scheme 6, R is a protective group of amino
group, and X and Y1 are the same as above.

[0224] In this step, the aldehyde group-containing compound shown in
Formula (6c) can be obtained in the same manner as in the first step of
Reaction Scheme 2 by using the aldehyde group-containing compound shown
in Formula (6b) instead of the ester group-containing compound shown in
Formula (2b).

[0225] Of the compounds of the present invention, compounds having
particular functional groups may be converted to other compounds of the
invention by chemically modifying these groups, as shown in the following
Reaction Scheme 7.

##STR00016##

[0226] In the above Reaction Scheme 7, V2 is a C0-3 alkylene
group or --CH═CH--, and R1, R6, R7, R8 and X are
the same as above. A C0 alkylene group means a single bond.

[0227] In this step, the carboxylic acid compound obtained by deprotecting
the ester group of the ester group-containing compound shown in Formula
(7a) by an ordinary, known method, or an active species thereof is
condensed in the same manner as in the first step of Reaction Scheme 1
with the amine compound represented by Formula (7b), or a salt thereof,
to obtain the amide compound shown in Formula (7c).

[0228] If one or more asymmetric carbons are present in the compound (I),
which is useful as an active ingredient of the medicine of the present
invention, optical isomers due to asymmetric carbon atoms (enantiomers
and diastereomers) and other isomers may be present. The present
invention encompasses isomers that have been isolated, and mixtures
thereof.

[0229] The compound (I), which is useful as an active ingredient of the
medicine of the present invention, encompasses pharmaceutically
acceptable prodrugs. Pharmaceutically acceptable prodrugs are compounds
having functional groups that can be converted, under chemical
conditions, such as solvolysis, or under physiological conditions, into
amino, hydroxyl, carboxyl, carbonyl, or like functional groups of the
compound (I), which is an active ingredient of the medicine of the
present invention. Representative functional groups of prodrugs include
the groups mentioned in "Iyakuhin no Kaihatsu [Development of
Pharmaceuticals]," Vol. 7, pp. 163-198, Hirokawa Publishing (1990).

[0231] The present invention further encompasses the hydrates, solvates,
and crystal polymorphs of the compound (I), which is useful as an active
ingredient of the medicine of the present invention, and pharmaceutically
acceptable salts thereof.

[0232] When a pharmaceutical composition contains the piperazine compound
or a salt thereof according to the present invention, a pharmaceutical
carrier can be added, if required, thereby forming a suitable dosage form
according to prevention and treatment purposes. Examples of the dosage
form include oral preparations, injections, suppositories, ointments,
patches, etc. Of these, oral preparations are preferable. Such dosage
forms can be formed by common preparation methods known to persons
skilled in the art.

[0233] As the pharmaceutical carrier, various organic or inorganic carrier
materials commonly used as preparation materials may be blended as an
excipient, binder, disintegrant, lubricant, or colorant in solid
preparations; or as a solvent, solubilizing agent, suspending agent,
isotonizing agent, buffer, or soothing agent in liquid preparations.
Moreover, a pharmaceutical preparation additive, such as an antiseptic,
anti-oxidant, colorant, sweetener, and stabilizer may also be used, if
required.

[0234] Oral solid preparations are prepared as follows. An excipient,
optionally together with a binder, disintegrant, lubricant, colorant,
sweetening/flavoring agent, etc., is added into the compound of the
present invention to produce tablets, coated tablets, granules, powders,
capsules, or the like, using an ordinary method.

[0241] Oral liquid preparations are produced as follows. A sweetening
agent, buffer, stabilizer, flavoring agent, etc., is added into the
compound of the present invention to produce an internal liquid medicine,
a syrup, an elixir, or the like using an ordinary method. In this case,
sweetening/flavoring agents as described above are usable. Examples of
buffers include sodium citrate, and examples of stabilizers include
tragacanth, gum arabic, and gelatin. If necessary, an enteric coating or
a coating to increase the persistence of effects can be provided by
methods known for oral preparations. Examples of coating agents include
hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose,
hydroxypropyl cellulose, polyoxy ethylene glycol, and Tween 80 (a
registered trademark).

[0242] Injections are prepared as follows. A pH adjuster, buffer,
stabilizer, isotonizing agent, topical anesthetic, etc., is added into
the compound of the present invention to produce a subcutaneous
injection, an intramuscular injection, or an intravenous injection using
an ordinary method. Examples of usable pH adjusters and buffers in this
case include sodium citrate, sodium acetate, and sodium phosphate.
Examples of usable stabilizers include sodium pyrosulfite, EDTA,
thioglycolic acid, and thiolactic acid. Examples of usable topical
anesthetics include procaine hydrochloride and lidocaine hydrochloride.
Examples of usable isotonizing agents include sodium chloride, glucose,
D-mannitol, and glycerin.

[0243] Suppositories are prepared as follows. A pharmaceutical carrier
known in the art, such as polyethylene glycol, lanolin, cacao butter, and
fatty acid triglyceride, is added into the compound of the present
invention, optionally together with Tween 80 (a registered trademark) or
a like surfactant, followed by production using an ordinary method.

[0244] Ointments are prepared as follows. An ordinary base, stabilizer,
wetting agent, preservative, etc., is added as required into the compound
of the present invention, and mixed and formulated using an ordinary
method. Examples of bases include liquid paraffin, white petrolatum,
white beeswax, octyldodecyl alcohol, and paraffin. Examples of
preservatives include methyl parahydroxybenzoate, ethyl
parahydroxybenzoate, and propyl parahydroxybenzoate.

[0245] Patches can be prepared by coating a general support with the above
ointment, cream, gel, paste, etc., using an ordinary method. Examples of
supports include woven or nonwoven fabrics made from cotton, staple
fibers, and chemical fibers; and films and foam sheets of soft vinyl
chloride, polyethylene, and polyurethane.

[0246] The amount of the compound of the present invention to be contained
in such a dosage unit form varies depending on the condition of the
patient or on the dosage form. The desirable amount in one dosage unit
form is about 0.05 to about 1,000 mg in the case of an oral preparation,
about 0.01 to about 500 mg in the case of an injection, and about 1 to
about 1,000 mg in the case of a suppository.

[0247] The daily dose of the medicine in such a dosage form depends on the
condition, body weight, age, gender, etc., of the patient. For example,
the daily dose for an adult (body weight: 50 kg) may be generally about
0.05 to about 5,000 mg, and preferably 0.1 to 1,000 mg, and is preferably
administered in one or in two to three divided doses per day.

[0248] Since the H-PGDS inhibiting action is attained in mammals, and
especially humans, by administrating a medicine containing the compound
of the present invention, the compound of the present invention is useful
in treating, preventing, or improving diseases caused by PGD2 generated
by the synthase or metabolite thereof. Examples of diseases to be
treated, prevented, or improved by a medicine containing the compound of
the present invention include allergic disease such as bronchial asthma,
pollinosis, allergic rhinitis, sinusitis, otitis media, allergic
conjunctivitis, spring catarrh, atopic dermatitis, contact dermatitis,
and food allergies.

[0250] The medicine containing the compound of the present invention is
expected to prevent exacerbation of Alzheimer disease or brain damage,
and/or improve the prognosis after brain damage. In addition, since it
can inhibit cell neoplastic transformation and metastatic tumor growth,
it is also useful in cancer therapy.

[0251] Moreover, it is useful in the treatment and/or prevention of
proliferative disorders due to PGD2 or its metabolites, such as
fibroblast proliferation, diabetic retinopathy, and tumor angiogenesis.
Furthermore, since it can suppress PGD2-induced smooth muscle
contraction, it can also be used in the treatment and/or prevention of
infertility, dysmenorrhea, premature delivery, and
eosinophile-leucocyte-related disorders.

EXAMPLES

[0252] The present invention is described in detail below with reference
to Reference Examples, Examples, and Test Examples, which are not
intended to limit the scope of the invention.

[0253] In the following description, 1H-NMR spectra were measured
using TMS (tetramethylsilane) as an internal standard, and the chemical
shifts are indicated by δ (ppm). With respect to the chemical
shifts, absorption patterns, coupling constants (J), and numbers of
protons are indicated in parentheses.

[0254] The following symbols are used for absorption patterns: s=singlet,
d=doublet, t=triplet, q=quartet, dd=double doublet, m=multiplet,
br=broad, and brs=broad singlet.

[0255] Moreover, the following symbols are used for structural formulas of
compounds: Me=methyl and Et=ethyl.

Example 1(1)

4-(4-aminopiperidin-1-yl)-benzoic acid tert-butyl ester

[0256] 4-fluorobenzoic acid tert-butyl ester (19.6 g, 100 mmol) was
dissolved in dimethyl sulfoxide (hereinafter referred to as DMSO) (50
ml), and potassium carbonate (20.7 g, 150 mmol) and 4-aminopiperidine
(11.0 g, 110 mmol) were added thereto, followed by stirring at
120° C. for 17 hours. After the reaction mixture was cooled to
room temperature, water was added to the mixture, and the precipitate was
collected by filtration, thereby obtaining
4-(4-aminopiperidin-1-yl)-benzoic acid tert-butyl ester (23.3 g, 84%) as
a milky-white solid.

[0258] 4-nitrophenyl chloroformate (2.42 g, 12 mmol) was dissolved in
tetrahydrofuran (hereinafter referred to as THF) (50 ml), and a THF (30
ml) solution of the 4-(4-aminopiperidin-1-yl)-benzoic acid tert-butyl
ester (2.76 g, 10 mmol) obtained in Example 1(1) was added dropwise at
-30° C. After stirring for 30 minutes at the same temperature,
1-[(1-methyl-1H-pyrrol-2-yl)carbonyl]piperazine hydrochloride (2.53 g, 11
mmol) and triethylamine (5.6 ml, 40 mmol) were added to the mixture,
followed by stirring at room temperature for 15 hours. A saturated sodium
bicarbonate aqueous solution was added to the reaction mixture, followed
by extraction with ethyl acetate. The organic layer was washed with water
and saturated sodium chloride, and then dried over anhydrous sodium
sulfate. After the desiccant was filtered off, the residue obtained by
evaporation under reduced pressure was purified using medium-pressure
silica gel flash column chromatography (methanol:chloroform=0:1 to 1:30),
thereby obtaining
4-(4-(4-((1-methylpyrrol-2-yl)-carbonyl)-1-piperazinecarbamoyl)piperidin--
1-yl)-benzoic acid tert-butyl ester (3.73 g, 75%) as a milky-white solid.

[0260] The 4-(4-(4-((1-methylpyrrol-2-yl)-carbonyl)-1-piperazinecarbamoyl)-
piperidin-1-yl)-benzoic acid tert-butyl ester (2.48 g, 5.0 mmol) obtained
in Example 1(2) was dissolved in formic acid (10 ml), followed by
stirring for 5 hours at 60° C. Water was added to the residue
obtained by concentration under reduced pressure, and the precipitate was
collected by filtration, thereby obtaining
4-(4-(4-((1-methylpyrrol-2-yl)-carbonyl)-1-piperazinecarbamoyl)piperidin--
1-yl)-benzoic acid (2.12 g, 97%) as a milky-white solid.

[0264] Following the procedure of Example 2, aminoethylmorpholine was used
instead of 3-aminomethylpyridine, thereby obtaining
4-((1-methylpyrrol-2-yl)-carbonyl)-N-(1-(4-(2-morpholinoethylcarbamoyl)-p-
henyl)-piperidin-4-yl)-1-piperazinecarboxamide (62%) as a milky-white
solid.

[0266] Following the procedure of Example 2, morpholine was used instead
of 3-aminomethylpyridine, thereby obtaining
4-((1-methylpyrrol-2-yl)-carbonyl)-N-(1-(4-(4-morpholinylcarbonyl)phenyl)-
-piperidin-4-yl)-1-piperazinecarboxamide (52%) as a milky-white solid.

[0268] Following the procedure of Example 2, piperidine was used instead
of 3-aminomethylpyridine, thereby obtaining
4-((1-methylpyrrol-2-yl)-carbonyl)-N-(1-(4-(1-piperidinylcarbonyl)phenyl)-
-piperidin-4-yl)-1-piperazinecarboxamide (68%) as a milky-white solid.

[0270] Following the procedure of Example 2, pyrrolidine was used instead
of 3-aminomethylpyridine, thereby obtaining
4-((1-methylpyrrol-2-yl)-carbonyl)-N-(1-(4-(1-pyrrolidinylcarbonyl)phenyl-
)-piperidin-4-yl)-1-piperazinecarboxamide (72%) as a milky-white solid.

[0274] The 4-(4-aminopiperidin-1-yl)-benzoic acid ethyl ester (15.7 g,
63.2 mmol) obtained in Example 7(1) was dissolved in THF (200 ml), and a
2M sodium carbonate aqueous solution (63 ml) was added thereto.
Subsequently, benzyloxycarbonyl chloride (11.7 ml, 82.2 mmol) was added
thereto, followed by stirring at room temperature for 2 hours. Water was
added to the reaction mixture, followed by extraction with ethyl acetate.
The organic layer was washed with water and saturated sodium chloride,
and then dried over anhydrous sodium sulfate. After the desiccant was
filtered off, the solid obtained by evaporation under reduced pressure
was collected by filtration and dried under reduced pressure, thereby
obtaining 4-(4-benzyloxycarbonylaminopiperidin-1-yl)-benzoic acid ethyl
ester (18.0 g, 74%) as a white solid.

[0276] The 4-(4-benzyloxycarbonylaminopiperidin-1-yl)-benzoic acid ethyl
ester (13.6 g, 35.6 mmol) obtained in Example 7 (2) was dissolved in
dichloromethane (150 ml), and a diisobutylaluminum hydride-hexane
solution (91 ml, 89.0 mmol) was added thereto, followed by stirring at
-78° C. for 1 hour. Methanol was added to the reaction mixture,
and then saturated sodium chloride was added thereto, followed by
stirring. After the insoluble material was filtered with Celite, the
solvent was evaporated from the filtrate under reduced pressure. The
obtained residue was dissolved in dichloroethane (180 ml), and manganese
dioxide (38.0 g) was added thereto, followed by stirring at 60° C.
for 21 hours. After the insoluble material was filtered with Celite, the
solvent was evaporated from the filtrate under reduced pressure, thereby
obtaining 4-(4-benzyloxycarbonylaminopiperidin-1-yl)-benzaldehyde (7.0 g,
58%) as a white solid.

[0278] Methoxymethyltriphenylphosphonium chloride (16.2 g, 47.3 mmol) was
dissolved in THF (300 ml), and an n-butyllithium-hexane solution (29.0
ml, 45.4 mmol) was added dropwise at 0° C., followed by stirring
for 30 minutes. Subsequently, the
4-(4-benzyloxycarbonylaminopiperidin-1-yl)-benzaldehyde (3.2 g, 9.46
mmol) obtained in Example 7(3) was added thereto, followed by stirring at
room temperature for 17 hours. A saturated sodium bicarbonate aqueous
solution was added to the reaction mixture, followed by extraction with
chloroform. The solvent was evaporated from the organic layer under
reduced pressure, and the obtained residue was purified using
medium-pressure silica gel flash column chromatography (NH silica gel,
ethyl acetate:hexane=1:4), thereby obtaining a crude enol ether as a
mixture. The obtained mixture was dissolved in ethyl acetate (30 ml), and
a 6N hydrochloric acid aqueous solution (6.0 ml) was added thereto,
followed by stirring for one hour. The reaction mixture was neutralized
with the addition of a saturated sodium bicarbonate aqueous solution,
followed by extraction with chloroform. The solvent was evaporated from
the organic layer under reduced pressure. The obtained residue was
dissolved in THF (15 ml) and methanol (15 ml), and sodium borohydride
(155 mg, 4.09 mmol) was added thereto, followed by stirring at 0°
C. for 1 hour. After a saturated ammonium chloride aqueous solution was
added to the reaction mixture, water was added to the residue obtained by
concentration under reduced pressure. The precipitate was collected by
filtration, thereby obtaining
N-(4-(2-hydroxyethyl)phenyl)-4-benzyloxycarbonylaminopiperidine (960 mg,
29%) as a white solid.

[0280] The N-(4-(2-hydroxyethyl)phenyl)-4-benzyloxycarbonylaminopiperidine
(1.38 g, 3.89 mmol) obtained in Example 7 (4) was dissolved in pyridine
(7.5 ml), and p-toluenesulfonyl chloride (960 mg, 5.04 mmol) was added
thereto under ice-cooling, followed by stirring for 4 hours. Water was
added to the reaction mixture, and the precipitate was collected by
filtration, thereby obtaining
N-(4-(2-tosyloxyethyl)phenyl)-4-benzyloxycarbonylaminopiperidine (1.35 g,
68%) as a yellow solid.

[0282] 1,2,3-triazole (3.4 ml, 58.6 mmol) was added to the
N-(4-(2-tosyloxyethyl)phenyl)-4-benzyloxycarbonylaminopiperidine (3.0 g,
5.90 mmol) obtained in Example 7(5), followed by stirring at 90°
C. for 2 hours. Methanol was added to the reaction mixture. The mixture
was refluxed under heat for 1 hour, and then allowed to cool to room
temperature. The precipitate was collected by filtration, thereby
obtaining N-(4-(2-(1,2,3-triazol-1-yl)-ethyl)-phenyl)-4-benzyloxycarbonyl-
aminopiperidine (1.3 g, 54%) as a white solid.

[0284] The N-(4-(2-(1,2,3-triazol-1-yl)-ethyl)-phenyl)-4-benzyloxycarbonyl-
aminopiperidine (1.3 g, 50 mmol) obtained in Example 7 (6) was dissolved
in methanol (13 ml) and THF (13 ml), and 10% palladium-carbon
(hereinafter referred to as Pd--C) (130 mg) was added, followed by
stirring at room temperature in an atmosphere of hydrogen gas for 24
hours. After the insoluble material was filtered with Celite, the solvent
was evaporated from the filtrate under reduced pressure, thereby
obtaining N-(4-(2-(1,2,3-triazol-1-yl)-ethyl)-phenyl)-4-aminopiperidine
(870 mg, 99%) as a white solid.

[0286] Following the procedure of Example 1(2),
N-(4-(2-(1,2,3-triazol-1-yl)-ethyl)-phenyl)-4-aminopiperidine was used
instead of 4-(4-aminopiperidin-1-yl)-benzoic acid tert-butyl ester,
thereby obtaining
4-((1-methylpyrrol-2-yl)-carbonyl)-N-(1-(4-(2-(1,2,3-triazol-1-yl)-ethyl)-
-phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (46%) as a milky-white
solid.

[0288] 4-fluorobenzaldehyde (37 g, 0.30 mol) was dissolved in DMSO (300
ml), and potassium carbonate (124 g, 0.89 mol) and
4-tert-butoxycarbonylaminopiperidine (66 g, 0.33 mol) were added thereto,
followed by stirring under heat at 120° C. for 12 hours. Triethyl
phosphonoacetate (134 g, 0.60 mol) was added to the reaction mixture,
further followed by stirring under heat for 2.5 hours. Water (900 ml) was
added to the reaction mixture. After cooling to room temperature, the
precipitate was collected by filtration and washed with water (300 ml)
and hexane (300 ml), thereby obtaining
4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-cinnamic acid ethyl ester
(110 g, 99%) as a white solid.

[0294] Following the procedure of Example 7(5),
N-(4-(3-hydroxypropyl)phenyl)-4-tert-butoxycarbonylaminopiperidine was
used instead of
N-(4-(2-hydroxyethyl)phenyl)-4-benzyloxycarbonylaminopiperidine, thereby
obtaining N-(4-(3-tosyloxypropyl)phenyl)-4-tert-butoxycarbonylaminopiperi-
dine (59%).

[0300] Following the procedure of Example 1(2),
N-(4-(3-(1,2,4-triazol-1-yl)-propyl)-phenyl)-4-aminopiperidine was used
instead of 4-(4-aminopiperidin-1-yl)-benzoic acid tert-butyl ester,
thereby obtaining
4-((1-methylpyrrol-2-yl)-carbonyl)-N-(1-(4-(3-(1,2,4-triazol-1-yl)-propyl-
)-phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (45%) as a white solid.

[0302] Following the procedures of Example 8(5) and Example 8(6),
3,5-dimethyl-1,2,4-triazole was used instead of 1,2,4-triazole, thereby
obtaining N-(4-(3-(3,5-dimethyl-1,2,4-triazol-1-yl)-propyl)-phenyl)-4-ami-
nopiperidine (52%) as a white solid.

[0306] Following the procedure of Example 8(5), 1,2,3-triazole was used
instead of 1,2,4-triazole, thereby obtaining
N-(4-(3-(1,2,3-triazol-1-yl)-propyl)-phenyl)-4-tert-butoxycarbonylaminopi-
peridine (33%) as a white solid.

[0308] Following the procedure of Example 8(6),
N-(4-(3-(1,2,3-triazol-1-yl)-propyl)-phenyl)-4-tert-butoxycarbonylaminopi-
peridine was used instead of
N-(4-(3-(1,2,4-triazol-1-yl)-propyl)-phenyl)-4-tert-butoxycarbonylaminopi-
peridine, thereby obtaining
N-(4-(3-(1,2,3-triazol-1-yl)-propyl)-phenyl)-4-aminopiperidine (83%) as
an oil.

[0310] Following the procedure of Example 1(2),
N-(4-(3-(1,2,3-triazol-1-yl)-propyl)-phenyl)-4-aminopiperidine was used
instead of 4-(4-aminopiperidin-1-yl)-benzoic acid tert-butyl ester,
thereby obtaining
4-((1-methylpyrrol-2-yl)-carbonyl)-N-(1-(4-(3-(1,2,3-triazol-1-yl)-propyl-
)-phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (42%) as a white solid.

[0316] Following the procedure of Example 8(6),
(3-(4-(4-tert-butoxycarbonylaminopiperidin-1-yl)-phenyl)-1-oxo-2-propen-1-
-yl)-morpholine was used instead of
N-(4-(3-(1,2,4-triazol-1-yl)-propyl)-phenyl)-4-tert-butoxycarbonylaminopi-
peridine, thereby obtaining
(3-(4-(4-aminopiperidin-1-yl)-phenyl)-1-oxo-2-propen-1-yl)-morpholine
(68%) as an oil.

[0318] Following the procedure of Example 1(2),
(3-(4-(4-aminopiperidin-1-yl)-phenyl)-1-oxo-2-propen-1-yl)-morpholine was
used instead of 4-(4-aminopiperidin-1-yl)-benzoic acid tert-butyl ester,
thereby obtaining
4-((1-methylpyrrol-2-yl)-carbonyl)-N-(1-(4-(3-morpholino-3-oxopropen-1-yl-
)-phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (64%) as a white solid.

[0322] 6-chloronicotinic acid ethyl ester (4.27 g, 23 mmol) was dissolved
in DMF (30 ml), and potassium carbonate (4.77 g, 35 mmol) and
4-aminopiperidine (2.76 g, 28 mmol) were added thereto, followed by
stirring at 80° C. for 3 hours and at 100° C. for 1 hour.
After the reaction mixture was cooled to room temperature, water was
added thereto, followed by extraction with ethyl acetate. The organic
layer was washed with water and saturated sodium chloride, and then dried
over anhydrous sodium sulfate. After the desiccant was filtered off, the
solvent was evaporated under reduced pressure, thereby obtaining
6-(4-aminopiperidin-1-yl)nicotinic acid ethyl ester (4.17 g, 73%) as a
pale brown oil.

[0326] The 6-(4-(4-((1-methylpyrrol-2-yl)-carbonyl)-1-piperazinecarbamoyl)-
piperidin-1-yl)-nicotinic acid ethyl ester (234 mg, 0.5 mmol) obtained in
Example 13(2) was dissolved in ethanol (1.5 ml) and THF (1.5 ml), and a
2M sodium hydroxide aqueous solution (1.4 ml, 2.8 mmol) was added
thereto, followed by stirring at room temperature for 5 hours. The
reaction mixture was neutralized with 2M aqueous hydrochloric acid,
followed by extraction with methanol:chloroform (1:9). The organic layer
was washed with water and saturated sodium chloride, and then dried over
anhydrous sodium sulfate. After the desiccant was filtered off, the
solvent was evaporated under reduced pressure, thereby obtaining
6-(4-(4-((1-methylpyrrol-2-yl)-carbonyl)-1-piperazinecarbamoyl)-piperidin-
-1-yl)-nicotinic acid (90%) as a milky-white solid.

[0328] The 6-(4-(4-((1-methylpyrrol-2-yl)-carbonyl)-1-piperazinecarbamoyl)-
-piperidin-1-yl)-nicotinic acid (132 mg, 0.3 mmol) obtained in Example 13
was dissolved in DMF (2.0 ml), and WSCD (69 mg, 0.36 mmol), HOBt (51 mg,
0.33 mmol), and morpholine (0.04 ml, 0.45 mmol) were added thereto,
followed by stirring under heat at 60° C. for 16 hours. After
cooling to room temperature, water was added to the reaction mixture,
followed by extraction with ethyl acetate. The organic layer was washed
with water and saturated sodium chloride, and then dried over anhydrous
sodium sulfate. After the desiccant was filtered off, the residue
obtained by evaporation under reduced pressure was purified using
medium-pressure silica gel flash column chromatography
(methanol:chloroform=1:50 to 1:15), thereby obtaining
4-((1-methylpyrrol-2-yl)-carbonyl)-N-(1-(5-(4-morpholinylcarbonyl)pyridin-
-2-yl)-piperidin-4-yl)-1-piperazinecarboxamide (24%) as a milky-white
solid.

[0330] Phenyl chloroformate (7.83 g, 50.0 mmol) was dissolved in
acetonitrile (100 ml), and a solution of the
4-(4-aminopiperidin-1-yl)-benzoic acid tert-butyl ester (13.82 g, 50.0
mmol) obtained in Example 1(1) in acetonitrile (50 ml) and DMA (50 ml)
was added dropwise under ice-cooling. Triethylamine (7.0 ml, 50.0 mmol)
was added thereto. After stirring at the same temperature for 2 hours,
water was added thereto, and the precipitate was collected by filtration,
thereby obtaining 4-(4-phenoxycarbonylaminopiperidin-1-yl)-benzoic acid
tert-butyl ester (15.5 g, 78%) as a milky-white solid. The obtained
4-(4-phenoxycarbonylaminopiperidin-1-yl)-benzoic acid tert-butyl ester
was used as is in the next reaction.

[0333] The 4-(4-((4-benzyloxycarbonyl)-1-piperazinecarbamoyl)piperidin-1-y-
l)-benzoic acid tert-butyl ester (5.23 g, 10.0 mmol) obtained in Example
15(2) was dissolved in formic acid (20 ml), followed by stirring at
60° C. for 3 hours. Water was added to the residue obtained by
evaporation under reduced pressure, and the precipitate was collected by
filtration, thereby obtaining
4-(4-((4-benzyloxycarbonyl)-1-piperazinecarbamoyl)piperidin-1-yl)-benzoic
acid (4.75 g, quant.) as a milky-white solid.

[0337] The 4-benzyloxycarbonyl-N-(1-(4-(2-morpholinoethylcarbamoyl)-phenyl-
)-piperidin-4-yl)-1-piperazinecarboxamide (14.5 g, 25.0 mmol) obtained in
Example 15(4) was dissolved in methanol (80 ml) and THF (80 ml), and 10%
Pd--C (3.0 g) was added thereto, followed by stirring at room temperature
in a hydrogen atmosphere for 17 hours. To the reaction mixture,
chloroform was added. After the insoluble material was filtered with
Celite, the filtrate was evaporated under reduced pressure, thereby
obtaining N-(1-(4-(2-morpholinoethylcarbamoyl)phenyl)-piperidin-4-yl)-1-p-
iperazinecarboxamide (11.2 g, quant.) as a milky-white solid.

[0339] 1-ethylpyrrole-2-carboxylic acid (139 mg, 1.0 mmol) was dissolved
in DMF (3.0 ml), and WSCD (230 mg, 1.2 mmol), HOBt (168 mg, 1.2 mmol),
and N-(1-(4-(2-morpholinoethylcarbamoyl)phenyl)-piperidin-4-yl)-1-piperaz-
inecarboxamide (400 mg, 0.9 mmol) obtained in Example 15(5) was added
thereto, followed by stirring under heat at 80° C. for 14 hours.
After the reaction mixture was allowed to cool to room temperature, a
saturated sodium bicarbonate aqueous solution was added to the reaction
mixture, followed by extraction with chloroform. The extract was washed
with water and saturated sodium chloride, and then dried over anhydrous
sodium sulfate. After the desiccant was filtered off, the residue
obtained by evaporation under reduced pressure was purified using
medium-pressure silica gel flash column chromatography
(methanol:chloroform=1:30 to 1:10), thereby obtaining
4-((1-ethylpyrrol-2-yl)-carbonyl)-N-(1-(4-(2-morpholinoethylcarbamoyl)phe-
nyl)-piperidin-4-yl)-1-piperazinecarboxamide (213 mg, 42%) as a
milky-white solid.

[0341] Following the procedure of Example 1 (2),
1-((1-ethyl-1H-pyrrol-2-yl)carbonyl)piperazine hydrochloride was used
instead of 1-((1-methyl-1H-pyrrol-2-yl)carbonyl)piperazine hydrochloride,
thereby obtaining
4-((1-ethylpyrrol-2-yl)-carbonyl)-N-(1-(4-(2-(1,2,3-triazol-1-yl)-ethyl)--
phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (75%) as a white solid.

[0343] Following the procedure of Example 15, corresponding carboxylic
acid was used instead of 1-ethylpyrrole-2-carboxylic acid, thereby
obtaining the title compound.

Method B

[0344] N-(1-(4-(2-morpholinoethylcarbamoyl)phenyl)-piperidin-4-yl)-1-piper-
azinecarboxamide obtained in Example 15(5) was suspended in THF and
chloroform, and triethylamine and corresponding acid chloride were added
thereto, followed by stirring at room temperature. A saturated sodium
bicarbonate aqueous solution was added to the reaction mixture, followed
by extraction with chloroform. The extract was washed with water and
saturated sodium chloride, and dried over anhydrous sodium sulfate. After
the desiccant was filtered off, the residue obtained by evaporation under
reduced pressure was purified using medium-pressure silica gel flash
column chromatography, thereby obtaining the title compound.

[0374] The synthesis was carried out according to the method disclosed in
International Publication WO2007-007778.

Test Examples

Test Example 1

Hematopoietic Prostaglandin D Synthase (H-PGDS) Inhibiting Action

[0375] The test was carried out according to the method of Urade, Y. et
al. (J. Biol. Chem., 262, 3820-3825, (1987)). More specifically, the
reaction mixture (49 μL) containing 100 mM Tris-HCl (pH 8.0), 1 mM
reduced glutathione, 0.1 mg/mL γ-globulin, and human H-PGDS (q.s.),
and a compound (final concentration: 0.01-100 μM) was preincubated at
25° C. for 5 minutes. A DMSO solution (final concentration: 1%)
was added to the solvent control group. Subsequently, 1 μL of
[14C] prostaglandin H2 (final concentration: 10 μM) was added to
start the reaction. One minute after the start of the reaction, 250 μL
of a reaction stop solution (diethylether/methanol/1 M citric acid
(30/4/1) at a temperature of -20° C. was added to stop the
reaction. After the reaction was stopped, 50 μL of the upper-layer
portion (organic solvent layer) was applied to a TLC plate and developed
at -20° C. for 45 minutes (developing solvent:
diethylether/methanol/acetic acid (90/2/1)). After drying the TLC plate,
the TLC plate was exposed to an imaging plate for 1 to 24 hours, and the
radioactivity corresponding to prostaglandin D2 (PGD2) was analyzed using
an image analyzer (produced by Fujifilm Corporation). The area (%)
occupied by the PGD2 band per lane was calculated to determine the
inhibition rate (%) of each Example compound at 0.1 μM relative to the
control group in each experiment, as well as the inhibition concentration
at 50% (IC50 value, nM) relative to H-PGDS. Tables 1 and 2 show the
results.

[0376] Reference Examples 1 to 11 are compounds in which the
(N-alkylpyrrol-2-yl)-carbonyl group, which characterizes the compounds of
the present invention, is replaced by another substituent such as a
heterocyclic ring. As shown in Table 1, the piperazine compound having an
(N-alkylpyrrol-2-yl)-carbonyl group as in the compounds of the present
invention showed a strong H-PGDS inhibitory effect, whereas Reference
Examples 1 to 11 showed little inhibitory effect.

[0377] Further, Reference Examples 12 to 16 are compounds having a
structure similar to that of the compounds of the present invention,
i.e., a structure comprising a fluorobenzoyl group and an aminocarbonyl
group, and having a high GST2 inhibitory activity (Range A). Reference
Example 17 is a compound comprising a fluoropyridinecarbonyl group and an
aminocarbonyl group, and is effective against metabolic syndrome in mice.
All of these compounds are disclosed in Patent Literature 3.

[0378] The compounds of the present invention clearly showed a stronger
H-PGDS inhibitory effect than Reference Examples 12 to 17.

Test Example 2

PGD2 Production Inhibiting Action in the Nasal Cavities of Guinea Pigs
with Antigen-Induced Rhinitis

[0379] A physiological saline solution containing 1 mg/mL of ovalbumin was
subcutaneously injected into the back of 5-week-old male Std: Hartley
guinea pigs in an amount of 1 mL/body for active sensitization (initial
sensitization). One week and two weeks after initial sensitization, 20
μL of a physiological saline solution containing 10 mg/mL of ovalbumin
was instilled into each nasal cavity using a micropipette (sensitization
by nasal administration). Three weeks after initial sensitization, 20
μL of a physiological saline solution containing 10 mg/mL of ovalbumin
was instilled into each nasal cavity using a micropipette to induce a
rhinitis reaction.

[0380] 30 minutes after the induction of a rhinitis reaction, the nasal
cavities were washed under pentobarbital sodium anesthesia. A nasal
cavity washing liquid (phosphate buffered saline containing 3 mM of EDTA
and 10 μM of indomethacin) was flushed using a Peristaltic Pump
(Gilson, Inc.) in the direction from the trachea to the upper respiratory
tract at a flow rate of 1 mL/min, and the liquid flowing out from the
nasal cavities was collected for 1 minute. The collected liquid was
centrifuged to separate the supernatant as the nasal cavity washing
fluid. The concentration of PGD2 in the nasal cavity washing fluid was
determined using an EIA kit (Prostaglandin D2-MOX EIA kit, Cayman
Chemical).

[0381] The test compound (30 mg/kg) was orally administered 1 hour before
induction of a rhinitis reaction. A formula to calculate the rate of
decrease in PGD2 in the nasal cavity washing fluid is shown below.

Rate (%) of decrease in PGD2 in the nasal cavity washing fluid={(PGD2
concentration in the control group-PGD2 concentration in the
compound-administered group)/(PGD2 concentration in the control
group-PGD2 concentration in the normal group)}×100

[0382] 8 or more cases were obtained from each group to determine whether
expression of the PGD2 production inhibiting action occurred, and the
PGD2 concentration in the nasal cavity washing fluid was compared between
the control group and each compound-administered group. Table 2 shows the
results. When the significance level was below 0.05, the action was
considered to be present and indicated by a symbol (*) in the table.
Reference Example 18, known as an H-PGDS inhibitor, was used as a
positive control substance.

[0383] According to the results in Table 2, the compound of the present
invention indicated a rate of decrease in the PGD2 concentration similar
to that of Reference Example 18 (these compounds have significant
differences). In contrast, Reference Examples 12 to 17 disclosed in
Patent Literature 3 did not show a significant decrease in the PGD2
concentration.